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Refractory Hypertension: Four Cases

Paul R. Chelminski, MD, MPH, FACP Associate Professor of Medicine Associate Residency Program Director

1.Review JNC-7 Guidelines 2.Understand common barriers to achieving blood pressure control 3.Review some causes of secondary hypertension. 4.Review recent advances in our understanding of the HTN management

JNC-7* Highlights
CVD risk doubles with each 20/10mmHg increment over 115/75 SBP more important CV risk factor Two or more agents usually required Thiazides are first choice and first line Consider 2 agents if BP >20/10 above goal Targets
140/90 130/80 if diabetic or CKD
*Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure, 7th Report http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf.

HTN Classification

Meds: Compelling Indications

HTN Control: Clinical Impact

Decreased CVD Incidence
Stroke:35-40% MI: 20-25% CHF: >50%

12mmHg BP reduction over 10 yrs will prevent one death in every 11 patients NNT is 9 patients with underlying CVD or target organ damage

BP Control in Clinical Settings

>70% non-diabetic & diabetic patients with sub-optimal control 91% adherent to regimens 70% taking fewer than 3 antihypertensives Therapeutic Inertia:
45% did not have therapy intensified at first f/u visit 36% had no change at 2nd f/u visit

Challenges to Improving Blood Pressure Control

Four Cases of Refractory Hypertension

Barriers to HTN control

Cost Medication side effects Lack of gratifying response to therapy (patient does not feel better) Need for lifestyle changes Tedium: titration- requiring multiple visits & close monitoring by MD & patient

Case 1
Visit 1 61 yo female with HTN, hyperparathyroidism, h/o DVT Presents with pins & needles in LEs Meds
coumadin, Sensipar amlodipine, lisinopril, furosemide, HCTZ, metoprolol

Social Hx: non-smoker,uninsured BP 194/129 (re-check, 172/111); ?nonadherence to one medication; recent SBPs ~140 Labs: Na 145, K 3.7, Cr 0.8, Ca 11.7, B12 465 Dispo: Restart meds & f/u 4 days

Case 1
Visit 2 c/o Fatigue Patient confirms medications BP 204/132 (re-check, 210/135) Receives clonidine in clinic & admitted for hypertensive urgency & management of hypercalcemia

Case 1
Hospitalization & Visit 3 Hydrated with decrease in Ca++ Source of HTN identified: non-adherence d/t inability to afford meds D/C Meds: lisinopril, metoprolol, furosemide (Walmart $4drugs to rescue) BP at f/u 147/101 Amlodipine added

Obstacles to Optimizing HTN Management

Cost Literacy!

Clinical Uncertainty
50% doctors dont intervene due to uncertainty about accuracy of triage BP (home blood pressures lower)

Competing Medical Demands

Trial evidence conflicting about influence of multiple comorbididities

Time constraints
Largely unstudied

Case 2
54 yo female with HTN, diabetes, hypercholesterolemia BP Meds: amlodipine, lisinopril, HCTZ spironolactone BP 7/09: 166/83; A1c 9.0%: Substitute chlorthalidone for HCTZ BP 1/09: 164/68; A1c: 7.3%: ?Nonadherence to one med

Case 2
Social Hx: No tobacco; no ETOH; h/o cocaine use but denies current.

Drugs That Cause HTN

Drugs of abuse
Cocaine, methamphetamine Alcohol

OTC decongestants Prescription

Venlafaxine/SNRIs Estrogens/OCPs Corticosteroids Namenda Erythropoietin Tacrolimus/Cyclosporin

Case 3
62 yo male with HTN, palpitations, myalgias Meds: felodipine (5mg), atenolol (100mg), benazepril (20mg), minoxidil (10mg prn elevated BP), KCL 80mEq/d Social: no tobacco; retired farmer ROS: no CP, no SOB/DOE, no syncope BP 182/99, P 64. +S4 gallop Labs: K+ 2.8; aldo 90, renin <0.2 (ratio=450)

Case 3
Dx: Hyperaldosteronism Etiology: Adrenal adenoma (rare malignancy), adrenal hyperplasia W/U:
Aldo/Renin: Ratio >30 suggests primary hyperaldosteronism MRI of abdomen

Medical: spironolactone ?Surgery

Case 3: Denouement
Spironolactone, 100mg bid started Orthostasis at home with SBPs in 70s Decreased minoxidil to 5mg/d and atenolol to 50mg/d BP 139/90 K+ (4.7)-palpitations, myalgias resolved.

Case 4 77yo female with refractory HTN, diet

controlled DM, obesity, OA

Case 4
BP 159/79 (Re-check, 160/79) ROS: Daytime sleepiness, snoring, nighttime arousals K+ 4.1, Cr 0.87 Sleep study: OSA Denouement: Awaiting outcome of CPAP trial


Study objective
Comparison of cardiovascular events between group treated with combination benazepril-HCTZ versus combination benazepril-amlodipine, with hypothesis that benazepril-amlodipine would be superior in reducing cardiovascular events.

Study design
Total 11,506 patients recruited for study Multi-center Randomized, double-blind trial Similar patient demographic and comorbidities in each group Intention to treat model

Who are the patients?

This study has a high predominance of patients who are elderly, obese, Caucasian, have multiple co-morbidities (including diabetes, dyslipidemia, and CAD), and difficult to control HTN, requiring multiple agents.
at high risk for cardiac events

Who are the patients?

38% Receiving 3 or more drugs at enrolment Only 37% had BP <140/70 60% had diabetes Average age 68yrs (fairly geriatric)

Patient randomized

Study procedures (contd)

Algorithm outlined by study for optimization of blood pressure control

20 mg benazepril 5 mg amlodipine

20 mg benazepril 12.5 mg HCTZ One month

40 mg benazepril 5 mg amlodipine BP > 140/90 without diabetes OR BP > 130/80 with diabetes No Yes Three months

40 mg benazepril 12.5 mg HCTZ BP > 140/90 without diabetes OR BP > 130/80 with diabetes Yes No

Continue current regimen

40 mg benazepril 10 mg amlodipine

40 mg benazepril 25 mg HCTZ BP > 140/90 without diabetes OR BP > 130/80 with diabetes

Continue current regimen

BP > 140/90 without diabetes OR BP > 130/80 with diabetes

Six months

Add other agents Eg beta blocker, alpha blocker, clonidine, spironolactone

Study Endpoints
Primary endpoint Time to first event One event per patient Composite of a cardiovascular event and death from cardiovascular causes Secondary endpoints Multiple events counted for a patient Including composite of cardiovascular events, hospitalization from heart failure, death from any cause

Results: Improved BP Control

Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood pressure control
Amlodipine Mean SBP Mean DBP % BP <140/90 131.6 73.3 75.4 HCTZ 132.5 74.4 72.4

Results: CV Mortality and Events

Benazepril/amlodipine group saw: Decreased primary endpoints at 30 mos. Decrease secondary endpoints: death from CV causes, non-fatal MI< stroke Early cessation of study by safety & monitoring committee when pre-specified thresholds for termination seen in Ace/CCB arm d/t efficacy

Kaplan-Meier Curve:
Time to First Primary Composite Endpoint

Results: Primary Endpoints

Primary endpoint at 30 months All Male Female Age >65 Age >70 +DM - DM Benazepril/ Amlodipine (%) 9.6 10.6 8.1 10.1 11 8.8 10.8 Benazepril/ HCTZ (%) 11.8 13.1 9.7 12.4 13.8 11 12.9 ARR (EER-CER) (%) 2.2 2.5 1.6 2.3 2.8 2.2 2.1 RRR (ARR/CER) (%) 19.6 19 16.4 18.5 20.2 20 16.2

Drug Costs
Drug name Cost for 30 day supply

Enalapril 5 mg -20 mg
HCTZ 12.5-25 mg Atenolol 25 mg- 100 mg Amlodipine (Norvasc) 5 mg

$4 $4 $75

Amlodipine (generic) 5 mg


Adapted from Blue Cross Blue Shield of North Carolina and WalMart $4 pharmacy list

90 supply available from Drugstore.com for $18